dbSNP rs876658502: ATM:p.Thr1029AsnfsTer19 (chr11-108272537-T-TA) – ACMG Classification: Pathogenic (18 pts)

Genes affected

ATM (HGNC:795): (ATM serine/threonine kinase) The protein encoded by this gene belongs to the PI3/PI4-kinase family. This protein is an important cell cycle checkpoint kinase that phosphorylates; thus, it functions as a regulator of a wide variety of downstream proteins, including tumor suppressor proteins p53 and BRCA1, checkpoint kinase CHK2, checkpoint proteins RAD17 and RAD9, and DNA repair protein NBS1. This protein and the closely related kinase ATR are thought to be master controllers of cell cycle checkpoint signaling pathways that are required for cell response to DNA damage and for genome stability. Mutations in this gene are associated with ataxia telangiectasia, an autosomal recessive disorder. [provided by RefSeq, Aug 2010]

ATM links:

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-108272537-T-TA is Pathogenic according to our data. Variant chr11-108272537-T-TA is described in ClinVar as [Pathogenic]. Clinvar id is 230318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4 link	c.3085dupA	p.Thr1029AsnfsTer19	frameshift_variant	Exon 21 of 63	ENST00000675843.1	NP_000042.3	Q13315A0A024R3C7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1 link	c.3085dupA	p.Thr1029AsnfsTer19	frameshift_variant	Exon 21 of 63		NM_000051.4	ENSP00000501606.1		Q13315

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1459460

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726260

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Ataxia-telangiectasia syndrome

Pathogenic:3

Mar 18, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ATM c.3085dupA (p.Thr1029AsnfsX19) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.3245_3247delinsTGAT (p.His1082fsX14), c.3712_3716delTTATT (p.Leu1238fsX6)). The variant was absent in 246070 control chromosomes (gnomAD) but has been reported in the literature in multiple compound heterozygous individuals affected with Ataxia-Telangiectasia (Keimling_2011, Micol_2011, Mitui_2005, Sandoval_1999, Teraoka_1999). These data indicate that the variant is very likely to be associated with disease. One publication reported the complete absence of ATM protein (analyzed by western blotting) in a lymphoblastoid cell line (LCL) derived from a patient who was compound heterozygote for this variant and another truncating ATM variant (Keimling_2011). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Thr1029Asnfs*19) in the ATM gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast cancer and ataxia telangiectasia (PMID: 9443866, 9887333, 10330348, 16266405, 29665859). This variant is also known as 3084insA, 3085insA, 3085_3086insA. ClinVar contains an entry for this variant (Variation ID: 230318). For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:3

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 18, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Observed in the heterozygous state in a patient with breast cancer (PMID: 29665859); Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 9887333, 9443866, 10330348, 16266405, 30612635, 37149759, 29665859) -

Apr 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ATM: PVS1, PM2, PS4:Moderate -

Hereditary cancer-predisposing syndrome

Pathogenic:3

Jan 23, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3085dupA pathogenic mutation, located in coding exon 20 of the ATM gene, results from a duplication of A at nucleotide position 3085, causing a translational frameshift with a predicted alternate stop codon (p.T1029Nfs*19). This mutation (also designated as c.3085_3086insA) has been reported in numerous individuals with Ataxia-Telangiectasia (A-T) (Telatar M et al. Am. J. Hum. Genet. 1998 Jan; 62(1):86-97; Teraoka S et al. Am. J. Hum. Genet. 1999 Jun; 64(6):1617-31; Sandoval N et al. Hum. Mol. Genet. 1999 Jan; 8(1):69-79; Mitui M et al. Ann. Hum. Genet. 2005 Nov; 69(Pt 6):657-64). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Sep 23, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant inserts 1 nucleotide in exon 21 of the ATM gene (also known as 3084insA, 3085insA, 3085_3086insA), creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with ataxia-telangiectasia (PMID: 9443866, 16266405, 10330348, 9887333). Additionally, it has been reported in an individual affected with breast cancer (PMID: 29665859) and an individual affected with anaplastic astrocytoma (PMID: 37149759). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of ATM function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic. -

Hauer Lab, Department Of Pediatric Oncology, Technical University Munich

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

ACMG/AMP, PVS1, PM2, PP5 -

Familial cancer of breast

Pathogenic:2

Jan 18, 2024

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -

Jan 17, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast

Pathogenic:1

Mar 21, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

ATM-related disorder

Pathogenic:1

Aug 03, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ATM c.3085dupA variant is predicted to result in a frameshift and premature protein termination (p.Thr1029Asnfs*19). This variant has been reported in individuals with ataxia telangiectasia (Table 2, referred to as c.3084insA, Telatar et al. 1998. PubMed ID: 9443866; Table 1, Sandoval et al. 1999. PubMed ID: 9887333; Table 2, Teraoka et al. 1999. PubMed ID: 10330348; Mitui et al. 2005. PubMed ID: 16266405; Table E1, Micol et al. 2011. PubMed ID: 21665257;). It has also been reported in an individual with breast cancer (Table 1, Renault et al. 2018. PubMed ID: 29665859). In vitro experimental studies indicate this variant impairs protein expression (Figure 1 and Table 1, Keimling et al. 2011. PubMed ID: 21778326). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. It is interpreted as pathogenic in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/230318/). This variant is interpreted pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

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SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

rs876658502

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over